The GPR55 receptor was cloned and first identified in 1999. It is a G protein-coupled transmembrane receptor. Although it shares only 14% homology with the CB1 and CB2 cannabinoid receptors, it was proposed as a new member of the endocannabinoid system. Indeed, cannabinoid receptor ligands were found to be able to activate the GPR55 receptor (GlaxoSmithKline WO0186305; AstraZeneca WO2004074844). Currently, there is controversy surrounding the pharmacology of GPR55. Today, GPR55 is still considered an orphaned receptor. However, endogenous lysophosphatidylinositol (LPI) derivatives have been reported to stimulate the GPR55 receptor in ERK1/2 phosphorylation assays in HEK293 cells overexpressing hGPR55. To date, there are very few GPR55 receptor specific agonists and/or antagonists. Some benzoylpiperazine derivatives were identified as GPR55 agonists with no action on the CB1 and CB2 cannabinoid receptors. A high screening pharmacological evaluation using β-arrestin assays in hGPR55-U2OS cells identified several families of GPR55 agonists and selective GPR55 antagonists that led to molecular modeling studies.
The GPR55 receptor has been shown to be involved in the processes of inflammatory pain, neuropathic pain, metabolic disorder, bone development, and tumor cell proliferation. Therefore, GPR55 is considered a biological target for the treatment of GPR55-related diseases such as diabetes, Parkinson's disease, multiple sclerosis, neuropathic pain, osteoporosis, cholangiocarcinoma, breast cancer, ovarian and prostate cancer, glioblastoma, and cutaneous carcinoma.
The compounds claimed in the present invention are chromenopyrazole-based structures. WO2010109050 describes chromenopyrazoles as cannabinoids with analgesic activity. More recently, in WO2014013117 and P201430372 chromenopyrazoles are described as antitumor drugs related to cannabinoid activity.